Process for preparing vitamin a esters

ABSTRACT

This invention is directed to a new and improved process for preparing vitamin A alcohol esters by treating 1-alkanoyloxy-6hydroxy or alkanoyloxy-3, 7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)-nonatriene-(2,4,7), with a halogenated hydrocarbon dissolved in an inert organic solvent having a high dipole moment.

United States Patent Weinstock [4 1 June 20, 1972 [21] App1.No.: 93,817

[52] U.S.Cl... ..260/49l,260/476B [51 Int. Cl. ..C07c 67/00 [58] Fieldof Search ..260/49 1 476 R [56] References Cited UNITED STATES PATENTS2,451,739 10/1948 lsler ..260/49l 9/1952 Lindler ..260/491 1/1970Kardysetal. ..260/491 Primary Examiner-Lorraine A. Weinberger AssistantExaminerVivian Garner Attorney-Samuel L. Welt, Jon S. Saxe, Bernard S.Leon, William H. Epstein and George M. Gould [57] ABSTRACT Thisinvention is directed to a new and improved process for preparingvitamin A alcohol esters by treating l-alkanoyloxyfi-hydroxy oralkanoyloxy-3,7-dimethyl-9-[2,6,6-trimethylcyclohexen-l-yl]-nonatriene-( 2,4,7), witha halogenated hydrocarbon dissolved in an inert organic solvent having ahigh dipole moment.

14 Claims, No Drawings BACKGROUND OF THE INVENTION In the past, vitaminA alcohol esters of the formula:

(3H,; (III;

CH CH wherein R is acyl; has been prepared by first reacting a compoundof the formula:

CH CH wherein R is hydrogen or acyl; and R is as above; dissolved in ahalogenated hydrocarbon having a high dipole moment with an aqueoushydrogen halide and then splitting off the hydrogen halide from theresulting halogen compound obtained by dehydrohalogenating with water ora base. This process is generally carried out at a temperature of about-35 C. for a period of about 5 minutes. Under these conditions optimumyields are obtained. I

SUMMARY OF THE INVENTION CH3 CH3 wherein X is halogen; and R is asabove; and then splitting off the hydrogen halide from the compound offormula III above.

By utilizing the process of this invention, remarkable reactionvelocities are achieved allowing reaction time of less than one second,even at -35 C. This short reaction time has the advantage of enablingthe process to be operated continuously by mixing, with an efficientmixing device, the halogenated hydrocarbon solution containing thecompound of formula II with the solution containing the hydrogen halidedissolved in the halogenated hydrocarbon solvent. By the process of thisinvention, only one half the quantity of hydrogen halide as thatrequired by former processes is needed to convert the compound-offormula II above to the compound of formula I in high yields.Additionally, the compound of formula II can be converted to thecompound of formula I by the process of this invention without thenecessity of utilizing extremely low temperatures. Therefore, thisprocess can be carried out utilizing only brine cooling which was notpossible when aqueous hydrogen halide was utilized to effect thisconversion. Also, the process of this invention provides the compound offormula I above in higher yields than can be obtained by utilizingaqueous hydrogen halide.

The phenomenon whereby vitamin A alcohol esters of formula I can beproduced almost instantaneously in higher yields from the compound offormula II utilizing a tempera ture of about room temperature is notcompletely understood. However, these beneficial results are directlyattributal to the use of hydrogen halide dissolved in a halogenatedhydrocarbon solvent. It has been found that the use of a halogenatedhydrocarbon solvent having -a high dipole moment rather than an aqueoussolvent for the hydrogen halide permits this conversion to occur almostinstantaneously to produce upon dehydrohalogenation the compound offormula I in high yields without the necessity for providing excessivecooling.

DETAILED DESCRIPTION OF THE INVENTION The term halogen as usedthroughout the disclosure is intended to encompass all four halogens,i.e., chlorine, fluorine, bromine and iodine with chlorine and brominebeing preferred. The term lower alkyl as used throughout the disclosurecomprehends both straight and branched hydrocarbon groups such asmethyl, ethyl, n-propyl, isopropyl and the like. The term acyl denotesan organic acid residue. The preferred organic acid residue are loweralkanoyl and aryl lower alkanoyl resides.

The term lower alkanoyl" denotes lower alkanoyl residues containing fromtwo to seven carbon atoms such as acetyl, propionyl, butyryl, etc. Theterm aryl" is employed herein is intended to connote preferentially aphenyl group or a substituted phenyl group such as a lower alkyl phenylgroup, preferably tolyl. The preferred aryl lower alkanoyl substituentis benzoyl.

The process of the present invention for the manufacture of vitamin Aalcohol esters of the formula I comprises first reacting a solution ofthe compound of the formula II in a halogenated hydrocarbon solventhaving a high dipole moment with a solution of a hydrogen halide in ahalogenated hydrocarbon solvent having a high dipole moment to form thecompound of the formula III. Therefore, the formation of the compound ofthe formula III is prepared in a substantially nonaqueous medium. Thecompound of formula III is then converted to the compound of formula Iby splitting off hydrogen halide therefrom in the presence of waterand/or a base.

The compounds of formula II which are utilized as starting materials inthe process of this invention are well-known materials. For instance,those compounds wherein R is an alkanoyl group and R is a hydrogen atomare described in Helvetica Chimica Acta, Vol. XXXII (1949) p. 489. Thecompound of formula II wherein R and R are both acyl radicals can beprepared by acylating a l,6-dihydroxy-3,7-dimethyl-92,6,6-trimethyl-cyclohexen-( l )-yl]-nonatriene-(2,4,7 This reaction canbe carried out by utilizing any of the conventional means of acylating ahydroxy group.

In carrying out the reaction .of this invention, any conventionalhalogenated hydrocarbon solvent having a high dipole moment can beutilized. Generally it is preferred that conventional halogenatedhydrocarbon solvents which have dipole moments of at least 1.18 .X 10*e. s. u. X cm. be utilized in this reaction. Especially preferred arethe halogenated hydrocarbon solvents which have dipole moments of from1.18 X 10' e. s. u. X cm. to about 1.74 X 10 e, s. u. X cm.

. Halogenated hydrocarbons which are used in the present process can bealiphatic or aromatic in character and are preferably chlorinatedhydrocarbons. Among the preferred halogenated hydrocarbon solvents areincluded chloroform, dichloromethane, dichloroethane, and chlorobenzenewith dichloromethane being especially preferred. Also, it is preferredto use the same halogenated hydrocarbon as solvent for the compound offormula II as the halogenated hydrocarbon solvent which is used for thehydrogen halide.

In carrying out this reaction, any of the hydrogen halides can beutilized. However, the preferred hydrogen halides are hydrogen bromideand hydrogen chloride, with hydrogen bromide being especially preferred.In carrying out the reaction of this invention, the hydrogen halidedissolved in the halogenated hydrocarbon solvent having a high dipolemoment is added to the compound of formula II dissolved in a halogenatedhydrocarbon solvent having a high dipole moment. The hydrogen halide isdissolved in the halogenated hydrocarbon having a high dipole momentprior to its addition to the compound of formula II. This hydrogenhalide solution generally contains from about 1 percent to about percentby weight of the hydrogen halide. In carrying out this reaction, atleast one mole of the hydrogen halide is present per mole of thecompound of formula II. Generally, it is preferred to utilize in thisreaction from about 1.0 moles to about 1.1 moles of the hydrogen halideper mole of the compound of formula II. If desired, large excesses ofthe hydrogen halide can be utilized in carrying out this reaction.However, since no additional beneficial results are achieved byutilizing large amounts of the hydrogen halide in carrying out thisreaction, these large excesses are seldom utilized.

This reaction can be carried out at a temperature of from about 45 C. toabout C. Generally, it is preferred to utilize a temperature of from 3 5C. to about 5 C.

The compound of fonnula III which is obtained by reacting the compoundof formula II with the hydrogen halide is converted into the desiredvitamin A ester of formula I by dehydrohalogenating the compound offormula III. Any conventional method of dehydrohalogenating a compoundof formula [II can be utilized in carrying out this step of the process.Generally, this dehydrohalogenating is carried out in the presence ofwater and/or a base. If it is desired to utilize a base, anyconventional base can be utilized. Among the conventional bases whichcan be utilized are alkali metal hydroxides such as sodium hydroxide;alkali metal carbonates such as sodium carbonate, potassium carbonate;alkali metal or alkaline earth metal oxides such as calcium oxide; ororganic bases such as pyridine and collidine. This reaction is carriedout in an aqueous medium. Furthermore, in carrying out this reaction,temperature and pressure are not critical and this reaction can becarried out at room temperature and atmospheric pressure. If desired,higher or lower temperatures can be utilized.

Alternatively, the dehydrohalogenation can be carried out by treatingthe compound of formula III with large amounts of water. In carrying outthis treatment, temperature and pressure are not critical and thedehydrohalogenation can take place at room temperature and atmosphericpressure. If desired, higher or lower temperatures can be utilized. Whenwater is utilized as the means for dehydrohalogenating the compound offormula III, the resulting product is neutralized with a base. Any ofthe conventional bases mentioned hereinbefore can be utilized incarrying out this neutralization reaction.

A particularly preferred embodiment to the present invention comprisesreacting a solution containing the compound of formula vII wherein R isacetyl and R is either hydrogen or acetyl in dichloromethane at atemperature of from 5 to -35 C. utilizing a solution of hydrogen bromidein dichloromethane. After forming the compound of formula III, thehydrogen bromide is split off by treating the compound of formula IIIwith aqueous sodium carbonate.

The instant process will be better understood by reference to thefollowing examples which are given for illustration purposes only andare not meant to limit the invention.

EXAMPLE 1 l ,6-Dihydroxy-3 ,7-dimethyl-9-[ 2,6,6-trimethyl-cyclohexen-(1 )-yl]-nonatriene-(2,4,7) was acetylated by conventional techniquessuch as by treatment with acetic anhydride or acetyl chloride in thepresence of a base followed by removal of the base by washing with anaqueous acid to yield a mixture of l-acetoxy-o-hydroxy andl,6-diacetoxy-3,7-dimethyl-9- [2,6,6 trimethyl-cyclohexen-( l)-yl]-nonatriene-(2,4,7).

EXAMPLE 2 250 ml. of a methylene chloride solution'containing 37.5 g. ofa mixture of l-acetoxy-6hydroxy and l,6-diacetoxy-3,7-dimethyl-9-[2,6,6-trimethyl cyclohexen-( l )-yl]-nonatriene- (2,4,7) and250 ml. of a solution of hydrogen bromide in methylene chloride werepumped into a mixing vessel cooled to -30 C. at approximately equalrates such that the residence time of the mixture in the reaction vesselwas 0.5-1 second [the concentration of the hydrogen bromide solution wasadjusted so that l. 1 moles of hydrogen bromide flowed for each mole ofthe mixture of l-acetoxy-o-hydroxy and l,6-

diacetoxy-3,7-dimethyl-9-[2,6,6-trimethyl-cyclohexen-( lyl]-nonatriene-(2,4,7)]. When about 400 ml. of effluent had beencollected in a quench vessel containing 400 ml. of aqueous solutioncontaining 10 percent by weight sodium carbonate, 0.2 ml. of pyridineand 0.1 g. of butylated hydroxytoluene pumping of the two solutions wasstopped, then the contents of the quench vessel were stirred at 3 C. for3 hours. The layers were then separated and the organic layer was washedwith 200 ml. of aqueous solution containing 5 percent by weight ofsodium bicarbonate. Both aqueous layers were backwashed with 200 ml. ofdichloro-methane and the combined organic layers were evaporated in thepresence of 0.25 ml. of aqueous solution containing 5 percent by weightof sodium bicarbonate and 0.2 ml. of pyridine using a water pump at 35C. Crystallization of the residue from methanol gave crystalline vitaminA acetate of 99.3 percent purity having a solidification point of 52.0C. The yield was 88.3 percent, based on the weight of1,6-dihydroxy-3,7-dimethyl-9- [2,6,6-trimethyl-cyclohexen-( l)-yl]-nonatriene-(2,4,7) used in the preparation of the startingmaterial.

EXAMPLE 3 The procedure described in Example 2 was carried out using asolution of hydrogen chloride in methylene chloride in place of asolution of hydrogen bromide in methylene chloride. The flow rate wasadjusted such that 1.1 mol of hydrogen chloride flowed for each mol ofthe mixture of lacetoxy-6-hydroxyand l,6-diacetoxy-3,7-dimethyl-9[2,6,6-trimethyl-cyclohexen-(l)-yl]-nonatriene-(2,4,7). The temperature in themixing zone was l0 C. After quenching for 24 hours at 20 C. and removalof solvent as described in Example 2, the residual oil was analyzed forvitamin A acetate by ultraviolet spectroscopy. The yield amounted topercent based on the weight of l,6-dihydroxy-3,7-dimethyl-9-[2,6,6-trimethyl-cyclohexen-(l)-yl]-nonatriene-( 2,4,7) used in the preparationof the starting material.

EXAMPLE 4l,6-Dihydroxy-3,7-dimethyl-9-[2,6,6-trimethyl-cyclohexen-(l)-yl]-nonatriene-(2,4,7)was treated with 1.5 mol of propionyl chloride in the presence of anorganic base and the mixture was subsequently worked up and washed withan aqueous acid to yield a mixture of l-propionoxy-o-hydroxyand1,6-dipr0pi0noxy-3 ,7-dimethyl-9-[ 2,6,6-trimethylcyclohexen-( l)-yl]-nonatriene-( 2,4,7

EXAMPLE 5 250 ml. of a methylene chloride solution containing 37.5 g. ofa mixture of l-propionoxy-G-hydroxyand1,6-dipropionoxy-3,7-dimethyl-9-[2,6,6-trimethyl-cyclohexen-( l )-yl]-nonatriene-(2,4,7) and 250 ml. of a solution of hydrogen bromide inmethylene chloride were reacted in the same manner as described inExample 2 [the flow rate being adjusted such that 1.1 mol of hydrogenbromide flowed for each mol of the mixture of l-propionoxy-6-hydroxyand1,6-dipropionoxy- 3,7-dimethyl-9-[2,6,6-trimethyl-cyclohexen-( l )'yl]-nonatriene-(2,4,7)] and the mixture was worked up as described inExample 2 to yield crude oil which was analyzed for.vitamin A propionatecontent by ultraviolet spectroscopy.

The yield amounted to 90 percent based on the weight of 1,6-dihydroxy-3,7-dimethyl-9-[2,6,6-trimethyl-cyclohexen-( lyl]-nonatriene-(2,4,7) used in the preparation of the starting material.

I claim:

1. A process for preparing a vitamin A alcohol ester of the formula:

CHa

wherein R is lower alkanoyl, phenyl-lower alkanoyl or loweralkyl-phenyl-lower alkanoyl; comprising reacting at a temperature offrom about -45 to about C., a compound of the formula:

wherein R is hydrogen or lower alkanoyl, phenyl-lower a1- kanoyl orlower alkyl-phenyl-lower alkanoyl; and R is as above; dissolved in ahalogenated hydrocarbon solvent having a high dipole moment of at leastl.8 l0' with a hydrogen halide selected from the group consisting ofhydrogen bromide and hydrogen chloride dissolved in a halogenatedhydrocarbon solvent having high dipole moment of at least l.8 l0 to forma halide ester of the fonnula:

CH: CH3

CH; OH: CH:

a dipole moment in the range of from 1.18 X 10 e.s. u. x cm. to about1.74 X l0 e. s. u. X cm.

5. The process of claim 4 wherein the solvent is dichloromethane.

6. The process of claim 1 wherein R is lower alkanoyl and R is hydrogenor lower alkanoyl.

7. The process of claim 6 wherein R is acetyl and R is hydrogen.

8. A process for preparing a halide ester of the formula:

wherein R is lower alkanoyl, phenyl-lower alkanoyl or loweraIkyLphenyI-lower alkanoyl and X is halogen selected from bromine andchlorine; comprising reacting at a temperature of from about 45 C. toabout 20 C. a compound of the formula:

CH CH I ona CH; -om

wherein R is as above and R is hydrogen or lower alkanoyl, phenyl-loweralkanoyl or lower alkylphenyl-lower alkanoyl; dissolved in a halogenatedhydrocarbon solvent having a high dipole moment of at least l.8 l0' witha hydrogen halide selected from the group consisting of hydrogen bromideand hydrogen chloride dissolved in halogenated hydrocarbon solventhaving a high dipole moment of at least 1.8Xl0

9. The process of claim 8, wherein said reaction is carried out at atemperature of from about 3 5 C. to about 5 C.

10. The process of claim 8 wherein said hydrogen halide is hydrogenbromide.

11. The process of claim 8 wherein both of said solvents have a dipolemoment in the range of from l. 18 X 10 e. s. u. X cm. to about 1.74 X l0e. s. u. cm.

12. The process of claim 1 wherein the solvent is dichloromethane.

13. The process of claim 8 wherein R is lower alkanoyl and R is hydrogenor lower alkanoyl.

14. The process of claim 13 wherein R is acetyl and R is hydrogen.

* i i i t

2. The process of claim 1 wherein said reaction is carried out at atemperature of from about -35* C. to about 5* C.
 3. The process of claim1 wherein said hydrogen halide is hydrogen bromide.
 4. The process ofclaim 1 wherein both of said solvents have a dipole moment in the rangeof from 1.18 X 10 18 e.s. u. X cm. to about 1.74 X 10 18 e. s. u. X cm.5. The process of claim 4 wherein the solvent is dichloromethane.
 6. Theprocess of claim 1 wherein R is lower alkanoyl and R'' is hydrogen orlower alkanoyl.
 7. The process of claim 6 wherein R is acetyl and R'' ishydrogen.
 8. A process for preparing a halide ester of the formula:wherein R is lower alkanoyl, phenyl-lower alkanoyl or loweralkyl-phenyl-lower alkanoyl and X is halogen selected from bromine andchlorine; comprising reacting at a temperature of from about -45* C. toabout 20* C. a compound of the formula: wherein R is as above and R'' ishydrogen or lower alkanoyl, phenyl-lower alkanoyl or loweralkyl-phenyl-lower alkanoyl; dissolved in a halogenated hydrocarbonsolvent having a high dipole moment of at least 1.8 X 10 18 with ahydrogen halide selected from the group consisting of hydrogen bromideand hydrogen chloride dissolved in halogenated hydrocarbon solventhaving a high dipole moment of at least 1.8 X 10
 18. 9. The process ofclaim 8, wherein said reaction is carried out at a temperature of fromabout -35* C. to about 5* C.
 10. The process of claim 8 wherein saidhydrogen halide is hydrogen bromide.
 11. The process of claim 8 whereinboth of said solvents have a dipole moment in the range of from 1.18 X10 18 e. s. u. X cm. to about 1.74 X 10 18 e. s. u. X cm.
 12. Theprocess of claim 1 wherein the solvent is dichloromethane.
 13. Theprocess of claim 8 wherein R is lower alkanoyl and R'' is hydrogen orlower alkanoyl.
 14. The process of claim 13 wherein R is acetyl and R''is hydrogen.